Migration as a Selection Paradigm for Primordial Germ Cells

项目总结 细胞异质性，即同一种群内细胞之间的离散差异，是公认的 作为恶性疾病的推动者。然而，细胞异质性对正常的贡献 发展才刚刚开始受到重视。相同细胞之间的微小差异的想法 类型能够确定细胞状态在考虑到 生殖系。精子的胚胎前体--原始生殖细胞之间的功能异质性 和卵细胞)从它们一开始就很明显；因为PGC单独地从它们的规范位置迁移到 性腺脊(Ginsburg等人，1990年；昆瓦尔等人，2006年)，它们扩散到早期迁徙的“领袖”和 后来迁徙的“落后者”(Gomperts等人，1994年)。此外，并不是所有的PGC都能长到性腺 岭；许多PGC在迁徙路线上死亡。性腺脊的成功殖民者维持着 为下一代贡献配子的潜力。体外细胞培养实验表明 与组织生态位无关，PGCs对单个细胞上不同的迁移信号表现出不同的信号反应 水平(Cantúet al.，2016)。这些迁徙潜力的差异表明，在 PGC的数量是内在决定的，但这些离散的细胞之间的差异如何影响 发展情况尚不清楚。领导者和落后者之间的区别可能通过有丝分裂而遗传， 转录上不同，并反映代谢功能的差异。这些初步数据推动了我的总体 假设PGC迁移选择性地倾向于更适合的PGC，而排除那些不适合的PGC。我 预计会失去稳定的、可遗传的表观遗传状态，不能进行代谢过程，或细胞损伤 可能使原生殖细胞不太适合，表现为转录水平上的RNA表达改变。这项建议 旨在表征生殖系细胞之间的异质性如何影响发育和生殖能力， 以及迁移是如何确保下一代只有最高质量的细胞存在的机制。 PGC是如何被选择来产生下一代的尚不清楚。理解PGC的基础 异质性和选择可以揭示发育如何限制配子和形状的传递 继承。因此，我建议成功定植新生性腺的生殖细胞不要这样做 随机机会，而是通过基于迁移的选择来确保最适合的细胞为未来做出贡献 物种谱系。

PROJECT SUMMARY Cellular heterogeneity, the discrete differences between cells within the same population, is recognized as a contributor to malignant conditions. However, the contribution of cellular heterogeneity to normal development is only beginning to be appreciated. The idea that minute differences among cells of the same type are capable of determining cell state is especially pertinent when considering the development of the germline. Functional heterogeneity among primordial germ cells (PGCs, the embryonic precursors to sperm and egg cells) is evident from their inception; as PGCs migrate individually from their site of specification to the gonadal ridges (Ginsburg et al., 1990; Kunwar et al., 2006), they spread into early migratory "Leaders" and later migratory "Laggards" (Gomperts et al., 1994). Additionally, not every PGC will make it to the gonadal ridge; many PGCs die along the migratory route. Successful colonizers of the gonadal ridge maintain the potential to contribute gametes to the next generation. Ex vivo cell culture experiments suggest that independent of tissue niche, PGCs exhibit signaling responses to migratory cues that vary at the single cell level (Cantú et al., 2016). These differences in migratory potential suggest that there may be subtypes within the population of PGCs that are intrinsically determined, but how these discrete cell-to-cell differences impact development is unknown. Distinctions between Leaders and Laggards may be heritable through mitosis, transcriptionally distinct, and reflect differences in metabolic function. These preliminary data fuel my overall hypothesis that PGC migration acts selectively to favor more fit PGCs while excluding those that are less fit. I expect that loss of stable, heritable epigenetic states, inability undergo metabolic processes, or cell damage may render PGCs less fit, manifesting in altered RNA expression at the transcriptional level. This proposal aims to characterize how heterogeneities among germline cells impact development and reproductive capacity, and how migration is a mechanism to ensure only the highest quality cells are present for the next generation. How PGCs are selected to generate the next generation is not known. Understanding the basis of PGC heterogeneity and selection could reveal how development limits the transmission of gametes and shapes inheritance. Therefore, I suggest that PGCs that successfully colonize the nascent gonad do not do so by random chance, but rather through a migration-based selection to ensure the most fit cells contribute to future species lineage.